The invention relates to a new industrially useable process for preparing tropenol, optionally in the form of the acid addition salts thereof.
The compound tropenol is known from the prior art and has the following chemical structure: 
The compound may be used as a starting compound for preparing pharmacologically valuable compounds. For example, the compounds tiotropium bromide, ipratropium bromide or also BEA2108 may be mentioned in this context. These pharmacologically valuable substances are characterized by the following chemical structures: 
Because of the high degree of efficacy of the above compounds they have to be made available in as pure form as possible using efficient methods of synthesis. The stringent purity requirements, in particular, with which compounds intended for therapeutic use generally have to comply, demand the lowest possible levels of contaminant in the starting compounds. If materials which contain relatively high levels of impurities are used as starting compounds, purification of the end product is often difficult as any impurities introduced at the beginning often cannot easily be removed at later stages of synthesis or only at the expense of substantial losses of yield. This is particularly the case when the by-products or impurities present only differ slightly structurally from the main products in question.
Against this background the problem of the present invention is to provide a method of synthesis which allows industrial production of tropenol, preferably in the form of one of the acid addition salts thereof, in a good yield and particularly with a high degree of purity.
The problem defined above is solved by the invention described hereinafter.
The present invention accordingly relates to an industrial process for preparing tropenol of formula (I) 
optionally in the form of the acid addition salts thereof, characterized in that a compound of formula (II) 
wherein
R denotes a group selected from C1-C4-alkyl, C2-C6-alkenyl and C1-C4-alkylene-phenyl, each of which may be substituted by hydroxy or C1-C4-alkoxy,
optionally in the form of the acid addition salts thereof as well as optionally in the form of the hydrates thereof in a suitable solvent, is reacted with a formamide-acetal of formula (III) 
xe2x80x83wherein
Rxe2x80x2 denotes C1-C4-alkyl and Rxe2x80x3 denotes a group selected from C1-C4-alkyl and C1-C4-alkylene-phenyl, to obtain a compound of formula IV 
xe2x80x83wherein the groups R, Rxe2x80x2 and Rxe2x80x3 may have the meanings given above, this is then converted by decarboxylation into an ester of formula (V) 
xe2x80x83wherein R may have the meanings given above, and lastly this ester is saponified to obtain the compound of formula (I) which is optionally converted into an acid addition salt by reaction with a suitable acid.
Preferably, the present invention relates to an industrial process for preparing tropenol of formula (I), optionally in the form of the acid addition salts thereof, which is characterized in that a compound of formula (II) wherein R denotes C1 -C4-alkyl or C2-C4-alkenyl is used as starting material, optionally in the form of the acid addition salts thereof and optionally in the form of the hydrates thereof, and wherein, in the formamide-acetal of formula (III) used, the groups Rxe2x80x2 denote methyl or ethyl and the groups Rxe2x80x3 represent methyl, ethyl or propyl.
Most preferably, the present invention relates to an industrial process for preparing tropenol of formula (I), optionally in the form of the acid addition salts thereof, preferably in the form of its hydrochloride, which is characterized in that a compound of formula (II) wherein R denotes 1-propenyl, 2-propenyl, 1-buten-1-yl, 1-buten-2-yl, 1-buten-3-yl, 1-buten-4-yl, 2-buten-1-yl or 2-buten-2-yl is used as starting material, optionally in the form of the acid addition salts thereof as well as optionally in the form of the hydrates thereof and wherein in the formamide-acetal of formula (III) used the groups Rxe2x80x2 and Rxe2x80x3 represent methyl or ethyl, preferably methyl.
Most preferably, the compound of formula (II) used is the compound wherein R denotes 2-buten-2-yl. This compound is also known by the name meteloidin in the prior art.
The term C1-C4-alkyl within the scope of the present invention denotes branched or unbranched alkyl groups with up to 4 carbon atoms. Examples include methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl and tert-butyl. The term C1-C4-alkylene-phenyl within the scope of the present invention denotes phenyl which is linked via a branched or unbranched alkylene bridge having up to 4 carbon atoms. Examples include benzyl, phenyl-2-ethyl, phenyl-1-ethyl, phenyl-3-propyl, phenyl-2-propyl- etc. Both the C1-C4-alkyl groups and also the C1-C4-alkylene-phenyl groups may, unless otherwise specified, be substituted by one or more hydroxy and/or C1-C4-alkyloxy groups.
By C2-C6-alkenyl are meant within the scope of the present invention branched or unbranched alkenyl groups with 2 to 6 carbon atoms which have at least one double bond. Examples include vinyl, 1-propenyl, 2-propenyl, 1-buten-1-yl, 1-buten-2-yl, 1-buten-3-yl, 1-buten-4-yl, 2-buten-1-yl, 2-buten-2-yl, butadien-1-yl, butadien-2-yl etc.
Unless otherwise stated, within the scope of the present invention the term acid addition salts refers to the salts formed with the acids hydrochloric acid, hydrobromic acid, phosphoric acid, sulphuric acid, tetrafluoroboric acid or hexafluorophosphoric acid, preferably hydrochloric acid or hydrobromic acid.
According to the invention, the following procedure may be followed for performing the process for preparing tropenol according to the invention.
The compound of formula (III) is placed in a suitable reaction vessel.
Usually at least 1 mol of the compound (III) is used per mol of the compound of formula (II) to be reacted. Preferably, between 1.01 and 5.0 mol, preferably between 1.1 and 4.0 mol, most preferably between 1.5 and 3.0 mol of the compound (III) are put in per mol of the compound (III) to be reacted. Then the compound of formula (II) is added batchwise with stirring. After the addition has ended the mixture obtained is heated preferably to a temperature of above 40xc2x0 C., preferably more than 50xc2x0 C., most preferably more than 60xc2x0 C. In the course of the reaction the alcohol Rxe2x80x2xe2x80x94OH is released. It is preferably removed from the reaction equilibrium by distillation. This distillation may optionally be carried out under reduced pressure. If the compound of formula (III) used is the compound wherein Rxe2x80x2 denotes methyl, the temperature is preferably adjusted to a range from about 55-90xc2x0 C., more preferably from about 60-85xc2x0 C. After the reaction has ended the compound of formula (III) which was optionally used in excess is removed by distillation under reduced pressure. To do this the mixture obtained is preferably heated to a temperature of above 40xc2x0 C., preferably above 50xc2x0 C., and a vacuum of 100 mbar or less, preferably 60 mbar or less, most preferably 40 mbar or less is applied.
The residue remaining (crude product of general formula (IV)) is then taken up with stirring in a suitable solvent, preferably in a polar organic solvent, most preferably in a solvent selected from the group consisting of dimethylformamide, acetonitrile, dimethylacetamide and N-methylpyrrolidinone, most preferably dimethylformamide. For example 0.001 to 10 L, preferably 0.01 to 5 L, most preferably 0.05 to 1 L of solvent may be used per mol of the compound of formula (II) used in order to prepare this solution. Preferably at this point about 0.07 to 0.5 L of solvent are used per mol of the compound of formula (II) originally put in.
The solution thus obtained is then added, over a period of for example 10 minutes to 3 hours, preferably 20 minutes to 2 hours, to stirred acetic anhydride heated to a temperature of more than 70xc2x0 C., preferably more than 80xc2x0 C., preferably more than 90xc2x0 C., but not more than 139xc2x0 C. Most preferably, the acetic anhydride used is heated to a temperature of about 120-135xc2x0 C. According to the invention, for example, 1 to 10 mol, preferably 2 to 8 mol, most preferably about 3 to 6 mol of acetic anhydride are used per mol of the compound of formula (II) originally put in. Preferably, according to the invention, about 4 to 5 mol of acetic anhydride are used per mol of the compound of formula (II) put in. During this reaction CO2 is given off. After the addition has ended for example a further 0.0005 to 5 L, preferably 0.005 to 2,5 L, most preferably 0.025 to 0.5 L of the abovementioned solvent are added to the solution containing the compound of formula (IV) and the resulting mixture is stirred at constant temperature for a further 10 minutes to 6 hours, for example, preferably a further 30 minutes to 3 hours, most preferably a further 1 to 2 hours. Then all the liquid ingredients of the reaction mixture are eliminated by distillation at least 40xc2x0 C., preferably at least 50xc2x0 C., most preferably at about 55-70xc2x0 C. under reduced pressure, preferably at about 20 mbar or less, preferably at about 10 mbar or less.
The residue remaining is then taken up in a suitable solvent, preferably in water and/or a lower alcohol, selected from the group consisting of methanol, ethanol and isopropanol, most preferably water, ethanol or a mixture thereof. At this point preferably 0.1 to 3 L, most preferably about 0.5 to 2 L of one of the abovementioned alcohols mixed with for example 0.01 to 1 L, preferably 0.05 to 0.5 L of water are used as solvent, per mol of the compound of formula (II) originally put in.
To saponify the ester function of the compound of formula (V) now present in dissolved form this is combined with a suitable base. Suitable bases are preferably inorganic bases, selected from among the alkali or alkaline earth metal carbonates, alkali or alkaline earth metal alkoxides and alkali or alkaline earth metal hydroxides. Particularly preferred are the hydroxides of lithium, sodium, potassium and calcium, most preferably sodium or calcium. According to the invention sodium hydroxide is most preferably used as the base. The abovementioned bases may be used in pure form or, more preferably, in the form of aqueous concentrated solutions. If, for example, sodium hydroxide is used, which is the particularly preferred base, it is preferably added in the form of aqueous solutions with a concentration of at least 40 wt. %. It is essential to use at least stoichiometric amounts of base per mol of the compound of formula (II) originally put in. However, it is also possible to use the base in excess. Preferably, about 1.1 to 4 mol, preferably 1.5 to 3 mol, most preferably about 1.7 to 2.5 mol of the abovementioned base are used per mol of the compound of formula (II) originally used. The base may be added to the solution of the ester of formula (V) for example at a temperature in the range from 0 to 50xc2x0 C. However, after the base has been added it is preferable to heat the resulting reaction mixture to a temperature above 50xc2x0 C., most preferably above 60xc2x0 C. In a particularly preferred embodiment of the present invention, after all the base has been added, the reaction mixture obtained is refluxed with stirring for a period of about 15 minutes to 4 hours, preferably 30 minutes to 3 hours, most preferably 1 to 2 hours. Then the solvent is eliminated by distillation at least 40xc2x0 C., preferably at least 50xc2x0 C., most preferably at about 50-60xc2x0 C. under reduced pressure, preferably at about 80 mbar or less, preferably at about 60 mbar or less, most preferably at about 50 mbar or less.
The residue obtained is taken up in water. About 0.01 to 1, preferably about 0.1 to 1 L of water are used per mol of the compound of formula (II) originally put in. The tropenol is extracted from this mixture by means of a suitable, water-immiscible organic solvent, preferably using a solvent selected from the group consisting of toluene, methyl-tert-butylether, dichloromethane, chloroform, preferably dichloromethane. According to the invention, a total of between 0.5 and 5, preferably between 0.75 and 4 liters of organic solvent are used for the extraction per mol of the compound of formula (II) used. The extraction is carried out according to the invention between 3 and 8, preferably 4 to 6 times. After the extraction has ended the organic phases are combined and the organic solvent is distilled off in vacuo.
The crude product remaining is taken up in an organic solvent selected from among methanol, ethanol and isopropanol, preferably isopropanol. According to the invention between 0.1 and 4.0 liters, preferably between about 1 and 2 liters of this abovementioned solvent are used per mol of the compound of formula (II) originally used. The solution obtained is optionally filtered. The filtrate contains tropenol of formula (I) in the form of its free base. If the free base is to be used in the next reaction, the solvent is distilled off in vacuo at this point. The remaining free base can then be used in the next steps of the synthesis, without further purification. According to the invention, however, the free base of tropenol is preferably converted into one of the acid addition salts. By the acid addition salts of tropenol are meant, for the purposes of the present invention, the salts selected from among the hydrochloride, hydrobromide, hydrogen phosphate, hydrogen sulphate, tetrafluoroborate or hexafluorophosphate. The hydrobromide and hydrochloride salts are particularly preferred, while tropenol hydrochloride is of particular importance according to the invention. To prepare the acid addition salts the filtrate is cooled to a temperature in the range from xe2x88x9220xc2x0 C. to 20xc2x0 C., preferably in the range from xe2x88x9210xc2x0 C. to 15xc2x0 C. The suspension thus obtained is then combined with the corresponding acid needed to form the acid addition salts, namely the hydrochloride, hydrobromide, hydrogen phosphate, hydrogen sulphate, tetrafluoroborate or hexafluorophosphate. At least 1 mol of the acid in question should be used per mol of the compound of formula (II) originally used. It may be possible, within the scope of the processes according to the invention, to use the acid in excess (i.e. 1.1 to about 2-3 mol per mol of the base (II) originally used). According to the invention the hydrochloride of tropenol is preferably prepared. The hydrochloric acid required for this may be added either in the form of a solution or in gaseous form. Preferably, hydrogen chloride in gaseous form is added. One of the abovementioned acids is added to the solution of the free base of the tropenol (I) until a pH of 1 to 5, preferably 1.5 to 4, is obtained. After all the acid has been added stirring may optionally continue at constant temperature for a further 0.5 to 2 hours. Finally, the precipitated acid addition salt of tropenol is separated off and optionally washed with a solvent selected from among acetone, methylisobutylketone and methylethylketone, preferably acetone, and dried in vacuo or under an inert gas (such as nitrogen), optionally at elevated temperature.
As mentioned in the introduction, tropenol, which may be obtained by the preparation process according to the invention, is a valuable starting compound for preparing therapeutically active compounds such as for example tiotropium bromide, ipratropium bromide or BEA2108. Because of the high purity in which tropenol can be obtained according to the present invention, it is possible to prepare the abovementioned active substances in the specifications required for pharmaceutical use.
Accordingly, the present invention further relates to the use of tropenol, optionally in the form of the acid addition salts thereof, as a starting material for preparing therapeutically active compounds such as for example tiotropium bromide, ipratropium bromide or BEA2108, preferably tiotropium bromide.
The present invention further relates to the use of compounds of formula (II) 
wherein R may have the meanings given above, optionally in the form of the acid addition salts thereof as well as optionally in the form of the hydrates thereof, as a starting material for preparing therapeutically active compounds such as for example tiotropium bromide, ipratropium bromide or BEA2108, preferably tiotropium bromide.
Preferably, the present invention relates to the use of meteloidin, optionally in the form of the acid addition salts thereof, as well as optionally in the form of its hydrates, as a starting material for preparing therapeutically active compounds such as for example tiotropium bromide, ipratropium bromide or BEA2108, preferably tiotropium bromide.
The procedure illustrated in Diagram 1 may be used to prepare tiotropium bromide starting from tropenol. 
Starting from the tropenol (I) which may be obtained according to the invention, first tropenol di-(2-thienyl)-glycolate (VII) is formed by reacting with di-(2-thienyl)-glycolic acid derivatives (VI). This ester is converted by epoxidation of the olefinic double bond into the corresponding scopine ester (VIII), from which tiotropium bromide can be obtained by reacting with methyl bromide.
Therefore, in a particularly preferred aspect, the present invention relates to a process for preparing tiotropium bromide 
characterized in that in a first step a compound of formula (II) 
wherein R may have the meanings given above, optionally in the form of the acid addition salts thereof as well as optionally in the form of the hydrates thereof, is reacted in a suitable solvent with a formamide-acetal of formula (III) 
wherein
Rxe2x80x2 and Rxe2x80x3 may have the abovementioned meanings, to obtain a compound of formula IV 
xe2x80x83wherein the groups R, Rxe2x80x2 and Rxe2x80x3 may have the meanings given above, then this is converted by decarboxylation into an ester of formula (V) 
xe2x80x83wherein R may have the meanings given above, and this ester is saponified to obtain tropenol of formula (I), which is reacted, optionally in the form of the acid addition salts thereof, in a second step with an ester of formula (VI) 
xe2x80x83to obtain the tropenol ester of formula (VII) 
xe2x80x83which is epoxidised in a third step to obtain the scopine ester of formula (VIII) 
xe2x80x83and this is then quaternised in a fourth step using methylbromide to obtain tiotropium bromide.
The Examples that follow serve to illustrate some methods of synthesis carried out by way of example in order to prepare tropenol and the tiotropium bromide which may be obtained therefrom. They are intended solely as possible procedures, provided as an illustration, without restricting the invention to their content.